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SATuRN: Report 2011

Southern Africa Treatment and Resistance Network

PRELIMINARY REPORT 2011 01 Contents 03 Foreword 04 A survey of 20 years of primary drug resistance in South Africa 06 Surveillance of transmiEed HIV-‐1 drug resistance in South African

provinces from 2005-‐2009 08 HIV drug resistance in first and second line paNents in South Africa: EC

Free State and Pretoria cohorts 10 HIV-‐1 drug resistance at anNretroviral treatment iniNaNon in children

previously exposed to single-‐dose nevirapine 12 Lopinavir concentraNon measurement in plasma or hair are helpful to

exclude paNents with poor adherence to second line regimens in South Africa

14 Phenotypic resistance to etravirine in an HIV-‐1 subtype-‐C background 16 HIV clinical management: IntegraNng in a virtual format failure clinics

in southern Africa 18 SATuRN RegaDB drug resistance & clinical management report 20 Southern African HIV Clinical Management and Drug Resistance

Workshop

SATuRN: Report 2011


1

PRELIMINARY REPORT 2011 22 SATuRN and Life Technologies (ABI) partnership provide a discounted

HIV resistance genotyping system 23 SATuRN at the SA AIDS Conference 24 Acknowledgements: Funding, coordinaNng centre, secretariat and

collaborators 25 PublicaNons & abstracts

SATuRN: Report 2011 Southern Africa Treatment and Resistance Network

2

Foreword While policy makers, experts and advocates debate whether widespread anNretroviral therapy (ART) can reverse the direcNon of the epidemic, treatment is unequivocally saving lives across Africa (1). The massive scale up of ART as treatment, pre and post exposure prophylaxis are changing the course and outcomes of infecNon and transmission. SystemaNc research is necessary to track the impact of treatment and anNretroviral drugs on health, drug resistance, development, sustainability and governance in Africa. The Southern Africa treatment and Resistance Network (SATuRN) seeks to build innovaNve collaboraNons between researchers, clinicians and policy makers focused on the monitoring, evaluaNon and delivery of ART. We have developed an approach to virologic failure, delivering genotyping, interpretaNon and clinical management to remote clinics, without elaborate computer systems or infecNous diseases specialists at each clinic. Applying the concepts of telemedicine, laboratorians and specialists, in medical centers throughout the world can review cases, including clinical and resistance data contend provide feedback and advice to the physician/nurse managing the paNent at the primary clinic (more info on pages 16 to 18). This system also allows the collecNon of complete treatment and clinical informaNon to be used in surveys that can be harnessed to systemaNcally track the transmission and acquisiNon of drug resistance. Results from three se_ngs are seen on pages 4 to 9 in this report. 1. Bendavid E, BhaEacharya J. The President's Emergency Plan for AIDS Relief in Africa: an evaluaNon of outcomes. Ann Intern Med. 2009 May 19;150(10):688-‐95.

Another objecNve of the SATuRN project is to increase access to efficient, lower cost genotyping and drug resistance tesNng in Africa. To collect, curate, interpret and disseminate sequence and drug resistance data, we have installed in South Africa two of the best HIV drug resistance databases in the world (The Stanford HIV Drug Resistance Database and RegaDB Clinical Management and Drug resistance Database). These databases are public accessible at our bioinformaNcs servers (via www.bioafrica.net/saturn/ website). To advance access to drug resistance tesNng to paNents, providers and programs, we have been working with a network of academics laboratories to develop and implement a cheaper resistance genotype test. This acNvity has received support from Life Technologies, with the provision of a discount of 25% for reagents needed for resistance genotyping (please see page 22 of this report). SATuRN currently includes 24 research partners in southern Africa that support our iniNaNves and we have collated over 3,200 resistance genotypes linked to treatment and clinical informaNon. These datasets are open for researchers and post-‐graduate students through the submission of a data request and proposal to a research steering commiEee. We have also delivered training in drug resistance tesNng and management to nearly 1,000 physician and nurses in southern Africa. Our long-‐term goals are to expand clinical and laboratory training and capacity building to build research capacity and enhance treatment throughout Africa. Tulio de Oliveira, David Katzenstein and Christopher Seebregts on behalf of SATuRN.

SATuRN: Report 2011


3

A survey of 20 years of primary drug resistance in South Africa

IntroducMon: The development of HIV-‐1 drug resistance poses a major threat to sustaining the achievements of anNretroviral therapy (ART)programmes in Africa, parNcularly in se_ngs where limited resources prevent regular laboratory monitoring of responses to ART and complex ARV regimens. ObjecMve: To describe the trend in the prevalence of transmiEed drug resistance (TDR) in South Africa over the past 20 years and to compare the results obtained from the Africa Centre’s 2010 HIV surveillance in rural KwaZulu-‐Natal.

Data source and Methods: A comprehensive literature search was conducted on PUBMED to idenNfy papers published on the past 20 years in South Africa on drug resistance in treatment naïve paNents. The key search terms used were “ HIV-‐1 AND Drug resistance AND South Africa”. Seventy two (72) sero-‐posiNve samples from recent sero-‐converters from northern rural KwaZulu-‐Natal were genotyped. They were selected from parNcipants of Africa Centre’s 2010 annual adult populaNon based HIV surveillance.

Results: Eight published data sets (Pillay et al, 2002; Gordon et al, 2003; Bessong et al, 2005, 2006; Seioghe et al 2007; Jacobs et al, 2008; Pillay et al, 2008; Huang et al, 2009) were selected for analysis from a total of 32 HIV drug resistance studies. AddiNonal sequences published through non-‐drug resistance arNcles (Ma[hews et al, 2008) were also retrieved from Genbank and included in the analysis. The total number of sequences analyzed was 1650.

The prevalence in transmiEed drug resistance over the past 20 years has remained low. There was no evidence of transmiEed resistance prior to the year 2000 (n = 32). The year with the highest level was 2002 (6.67%, 95% confidence interval (CI):3.09-‐13.79%; n: 6/90). Aoer 2002, the prevalence remained below 5% (WHO low-‐level threshold) and did not significantly vary staNsNcally overNme. The Africa Centre’s transmiEed drug resistance surveillance among sero-‐converters idenNfied in the 2010 surveillance round showed a prevalence of 1.39%, 95% CI: 0.25-‐7.46% (n: 1/72).


4

SATuRN: Report 2011


Figure 2: Trend in the prevalence of TDR between 2000 and 2010

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N = 107 78 90 315 203 59 475 33 129 57 72

Figure: Trend in the prevalence of TDR between 2000 and 2010. The 2010 results were extracted from the Africa Centre’s transmiEed drug resistance surveillance among sero-‐converters and esNmated a prevalence of 1.39% (n=1/73). The unique individual had the NNRTI (Y181C) and NRTI (M184V) resistance mutaNon.

Poster with complete results at SA AIDS Conference: Manasa J, Cassol S, Seebregts C, Newell M-‐L, de Oliveira T. 20 years of primary drug resistance studies in South Africa. 5th SA AIDS Conference Poster (PS1-‐47: abstract 224).

5

Surveillance of Transmi[ed HIV-‐1 Drug Resistance in South African Provinces from 2005-‐2009

Background: Surveillance of HIV-‐1 transmiEed drug resistance (TDR) was conducted among pregnant women in South Africa over a 5 year period aoer the iniNaNon of a large naNonal anNretroviral treatment program.

Results: A total of 354 sequences were analyzed from 9 surveys. In GP, the levels of TDR were <5% for all drug classes while in KZN levels were <5% in 2007 but appeared to be increasing for NNRTI as these reached 5-‐15% in 2009. A total of 12 (3.4%) sequences had TDR including K103N and M184I/V. Use of the BED ELISA suggested that samples selected for inclusion into the study were enriched for those with incident infecNon.

Methods: All parNcipants were from Gauteng (GP) and KwaZulu-‐Natal (KZN) Provinces and were part of the 2005 to 2009 annual ante-‐natal HIV seroprevalence survey conducted by the NaNonal Department of Health. HIV-‐1 posiNve serum specimens were tested using the Aware™ BED™ EIA HIV-‐1 Incidence Test. TDR was assessed in primigravid women age <25 years. Genotyping was performed on viral RNA by sequencing the protease and reverse transcriptase genes.

Conclusions: Analysis of the levels of TDR in 2 provinces of South Africa over 5 years suggested that in GP, TDR remains low while in KZN TDR levels may be increasing with the most recent survey showing moderate levels of resistance to the NNRTI drug class. Serological tests for incident infecNons may be a useful addiNonal parameter to include in surveys of TDR.


6

SATuRN: Report 2011


Table: TransmiEed HIV Drug Resistance Threshold Surveys perform

ed in Gauteng and Kw

aZulu-‐Natal Provinces betw

een 2005 and 2009

7

References:

Pillay V, Ledwaba J, Hunt G, Rakgotho M, Singh B, Makubalo L, BenneE D, Puren A and Morris L. AnNretroviral drug resistance surveillance among drug-‐naïve HIV-‐1 infected individuals in Gauteng Province, South Africa in 2002 and 2004. An#viral Therapy 2008, 13: 101-‐107

Hunt GM, Ledwaba J, Basson AE, Moyes J, Cohen C, Singh B, Bertagnolio S, Jordan MR, Puren A and Morris L. Surveillance of TransmiEed HIV-‐1 Drug Resistance in South Africa from 2005-‐2009. CID 2011, submiEed

Mutational patterns

Province Year

Num

ber specim

ens tested

Num

ber sequences analyzed

Amplification

rate M

edian Age

(Range)

HIV

subtype N

umber

with

mutations

PI N

RTI

NN

RTI

Threshold level

2005 51

34 76%

21 (18-22)

C

0

<5% N

RTI, N

NR

TI 2006

40 34

93%

20 (18-21) C

0

<5%

all drug classes 2007

133 47

46%

20 (18-21) C

1

M46I

M184I

<5%

all drug classes 2008

43 34

81%

20 (18-21) C

0

<5%

all drug classes

Gauteng (G

P)

2009 58

47 81%

19 (18-21)

C (1A

) 1

M

184V

Y188L

<5% all drug classes

2005 287

40 14%

21 (18-24)

C

1

K

101E

Y181C

N

D*

2007 61

34 67%

19 (18-22)

C

0

<5% all drug classes

M46I

M

184V

K103N

K219R

K103N

2008 284

37 13%

20 (18-24)

C (1B

) 5

K103N

ND

*

K103N

V

106M

Kw

aZulu-N

atal (K

ZN)

2009 80

47 71%

19 (18-21)

C (1D

) 3

K101P

K

103N

<5% P

I, NR

TI 5-15%

NN

RTI

HIV drug resistance in first and second line paMents in South Africa: EC Free State and Pretoria cohorts.

IntroducMon: There has been a lack of effecNve interacNon between South Africa’s research and prevenNon/treatment policies. To facilitate exchange of informaNon between researchers and policy makers, SATuRN, in collaboraNon with researchers from the United States and Europe, has developed two HIV-‐1 drug-‐resistance databases (Stanford HIVdb and RegaDB) in southern Africa. These rapidly expanding databases (currently > 2,500 genotypes), which serve a resource for regional and global HIV-‐1 research, have the capacity to enhance the large scale systemaNc monitoring of anNretroviral rollout programs throughout southern Africa.

Data source and Methods: The databases are being populated with a large number of HIV-‐1 sequences from South Africa and neighbouring countries. Researchers in the University of the Free State (UFS) School of Medicine and the Departments of Family Medicine and Immunology at the University of Pretoria (UP) are instrumental in supplying data on paNents failing therapy. The UFS and UP component of the database currently consists of two datasets that provide detailed informaNon on the paNents’ treatment and clinical history, together with the paNents’ genotypic data.

Results: Free State 1st line: 116 of 131 (88.5%) paNents experiencing virological failure an average of 874 days aoer the iniNaNon of ART had resistance mutaNons. NRTI and NNRTI, the most prevalent mutaNons, were detected in 76.3% and 83.9% of paNents, respecNvely. M184V/I, the most common NRTI mutaNon, was present in 71.7% of paNents, followed by a range of NNRTI mutaNons (K013N, V106M, G190A, Y181CI) present at levels ranging from 43.5% to 17.6%. Although 17.6% of sequences contained TAMs, only 7.6% had more than two TAMs, which limit the effecNveness of second line regimens.

Pretoria 1st line: Analysis of 111 paNents (113 genotypes) failing first line (NRTI/NNRTI-‐based) ART indicated that 75.2% of sequences contained at least one NRTI or NNRTI mutaNon. M184V/I, the most prevalent resistance mutaNon, was detected in 71/113 genotypes (62.8%). This was followed, in order of decreasing prevalence, by mutaNons at K103N (40.7%), V106M (16.8%), G190A (16.8%) and Y181C (13.3%). At least one Thymidine Analog MutaNon (TAM) was detected in 23/111 (20.7%) of paNents.


8

SATuRN: Report 2011


Figure 2: Trend in the prevalence of TDR between 2000 and 2010 N = 107 78 90 315 203 59 475 33 129 57 72

Results to be presented at SA AIDS Conference and IAS 2011: Van Vuuren C, Goedhals D, Steyn D, Mamabolo MK, Monyane R, Murrell B, Cassol S, de Oliveira T, Seebregts C. Low Level of Protease Inhibitor (PI) Resistance in PaNents Failing Second Line Drug Regimens in the Free State Province of South Africa. Poster IAS 2011, Rome, Italy.

Goedhals D, Van Vuuren C, Steyn D, Mamabolo MK, Monyane R, Murrell B, Cassol S, de Oliveira T, Seebregts C. HIV Drug resistance in adult paNents failing first-‐line anNretroviral therapy (ART) in the Free State Province of South Africa. Poster IAS 2011, Rome, Italy.

Rossouw T, Mahasha P, Malherbe G, Manasa J, van Dyk G, Cassol S, Seebregts C, de Oliveira T SATuRN, the Southern African Treatment and Resistance Network: ApplicaNon to the Management and Surveillance of HIV-‐1 Drug Resistance in a Public Health Se_ng in Pretoria. Oral presentaNon SA AIDS Conference (Session 4, Track , Hall 6, 4-‐6pm, abstract number 229).

Rossouw T, Malherbe G, van Dyk G, Seebregts C, Feucht U, Cassol S and de Oliveira T for the FIRST HIV-‐1 Drug Resistance Study Team and SATuRN. HIV-‐1 Drug Resistance in South Africans Failing Protease Inhibitor (PI)-‐Based AnNretroviral Therapy (ART): ComparaNve Analysis of Adult vs. Pediatric PaNents. Poster SA AIDS Conference (PS1-‐26: 230).

Free State 2nd line: Resistance mutaNons were detected in 16/45 (35.5%) paNents experiencing virological failure on average 714 (interquarNle 245-‐955) days aoer iniNaNon to second line ART containing at least one PI. Major PI mutaNons were idenNfied in only 11.1% of paNents. NRTI, NNRTI and TAMs mutaNons were more common and present at a frequency of 24.4%, 22.2% and 8.9%, respecNvely.

Pretoria 2nd line: 8/17 (52.9%) adults and 3/33 (9.1%) children had no detectable resistance, suggesNng non-‐compliance. Major PI mutaNons (V32I, M46L, I47A, L90M) were detected in only of 1/17 (5.9%) adults compared to 7/33 (21.2%) pediatric paNents. 5/33 (15.1%) pediatric sequences contained >3 PI mutaNons. The most prevalent, M461 and V82A, were detected in 18.2% of sequences, followed by I54V, L24I, I50V and L76V at a frequency of 3.0% each. Children also had more NNRTI and NRTI mutaNons (39.4% vs 29.4%), especially those related to NVP (K103) and 3TC (M184V/I) (27.3% vs 17.7% and 75.8% vs. 29.4%, respecNvely).

9

HIV-‐1 drug resistance at anMretroviral treatment iniMaMon in children previously exposed to single-‐dose nevirapine

ObjecNve: To describe the prevalence of HIV-‐1 drug resistance mutaNons at the Nme of treatment iniNaNon in a large cohort of HIV-‐infected children previously exposed to single dose nevirapine (sdNVP) for prevenNon of transmission. Design: Drug resistance mutaNons were measured pre-‐treatment in 255 infants and young children under 2 years of age in South Africa exposed to sdNVP and iniNaNng ritonavir-‐boosted lopinavir-‐based therapy. Those who achieved viral suppression were randomized to either conNnue the primary regimen or to switch to a nevirapine-‐based regimen. Pre-‐treatment samples were tested using populaNon sequencing and real Nme allele-‐specific PCR (AS-‐PCR) to detect Y181C and K103N minority variants. Those with confirmed viremia >1000 copies/ml by 52 weeks post-‐randomizaNon in the switch group were defined as having viral failure.

Results: Non-‐nucleoside reverse transcriptase inhibitor (NNRTI) mutaNons, predominantly Y181C, were detected by either method in 62% of infants less than 6 months of age, in 39% of children 6-‐12 months of age, 22% 12-‐18 months, and 16% 18-‐24 months (p=<0.0001). NNRTI mutaNons detected by genotyping, but not K103N or Y181C mutaNons detected only by AS-‐PCR, were associated with viral failure in the switch group. Conclusions: The prevalence of mutaNons known to compromise primary NNRTI-‐based therapy is high in sdNVP-‐exposed children, supporNng current guidelines recommending use of PI-‐based regimens for young children. Standard genotyping is adequate to idenNfy children who could benefit from switching to NNRTI-‐based therapy


10

SATuRN: Report 2011


Figure: Overall prevalence of NNRTI mutaMons among 255 sdNVP-‐exposed children iniMaMng anMretroviral therapy. Data show the prevalence of NNRTI mutaNons by genotyping (black bars) plus the addiNonal prevalence when including samples that were only idenNfied using the Y181C or the K103N AS-‐PCR (grey bars). Samples classified as indeterminate by Y181C AS-‐PCR were excluded .

References: Coovadia A, Abrams EJ, Stehlau R, Meyers T, Martens L, Sherman G, Hunt G, Hu C-‐C, Tsai W-‐Y, Morris L and Kuhn L. Re-‐use of nevirapine in exposed HIV-‐infected children aoer Protease Inhibitor-‐based viral suppression. JAMA 2010, 304(10):1082-‐1090

Taylor BS, Hunt G, Abrams E, Coovadia A, Meyers T, Sherman G, Strehlau R, Morris L and Kuhn L. Rapid development of anNretroviral drug resistance mutaNons in HIV-‐infected children iniNaNng protease inhibitor-‐based therapy less than 2 years of age in South Africa. AIDS Res Hum Retroviruses 2011, 27: in press

Hunt GM, Coovadia A, Abrams EJ, Sherman G, Meyers T, Morris L and Kuhn L. HIV drug resistance at anNretroviral treatment iniNaNon in children previously exposed to single-‐dose nevirapine. AIDS 2010, in press

11

Phenotypic Resistance to Etravirine in an HIV-‐1 Subtype-‐C Background Background: South Africa has an esNmated 5.7 million people infected with HIV-‐1 of whom 919,923 were receiving anNretroviral treatment by the end of 2009. The first-‐line regimen includes a non-‐nucleoside reverse transcriptase inhibitor (NNRTI), either efavirenz or nevirapine. Both drugs share similar mutaNon profiles and exhibit cross-‐resistance. Here we examine the phenotypic sensiNvity of single and double NNRTI mutaNons found in paNents failing either nevirapine or efavirenz, to a second generaNon NNRTI, etravirine which has an unrelated resistance profile. Methods: Single and double NNRTI resistance mutaNons were introduced into an HIV-‐1 expression plasmid containing a ~3.7 kilo-‐base gag-‐pol insert from a subtype-‐C reference strain. The NNRTI mutaNon list from the InternaNonal AIDS Society was used for selecNon of single mutants. Double mutants with significant covariaNon were idenNfied by performing a Jaccard analysis on sequences from NNRTI experienced paNents. Mutant plasmids were transfected into 293T-‐cells for the producNon of HIV-‐1 resistance vectors, and used to infect 293T-‐cells in serial diluNons of efavirenz, nevirapine and etravirine. Fold-‐change (FC) values were deduced for each virus-‐drug combinaNon. Phenotypic resistance was classified by use of the Monogram PhenoSense™ and Virco AnNvirogram® cut-‐off values.

Results: Of the 30 single NNRTI mutaNons tested, only Y181I (FC>40) and Y181V (FC>40) caused high level resistance to etravirine. MutaNons K101E/P, E138A/K, Y181C, Y188L and M230L gave a low to intermediate level of resistance. MutaNons K101P, K103N, V106M, Y188L, G190S and M230L caused high-‐level resistance to efavirenz and nevirapine, while Y181C/I/V, Y188C/L and G190S conferred high-‐level resistance to nevirapine only. MutaNon V179F conferred hyper-‐suscepNbility to all three NNRTIs (FC=0.004-‐0.151). MutaNon Y188C, although conferring high level resistance to nevirapine (FC>40), conferred hypersuscepNbility to etravirine (FC=0.144). All eight double mutaNons caused high-‐level resistance to nevirapine (FC>40), and some to efavirenz. InteresNngly, the combinaNon of V179F with Y181C caused a high level of resistance to both etravirine (FC=>40) and nevirapine (FC>40). The Y181C and G190S double mutant was the only other combinaNon that caused high-‐level resistance to etravirine (FC>40). Conclusion: NNRTI resistance mutaNons, either singly or in combinaNon, that arise in response to nevirapine or efavirenz rarely conferred high levels of resistance to etravirine. However, the combinaNons of V179F/Y181C and G190S/Y188C conferred high level resistance to ETV, as has previously been predicted. As combinaNons are not prevalent in currently failing individuals, etravirine is a suitable opNon for first-‐line NNRTI-‐based regimen salvage.


12

SATuRN: Report 2011


13

>40

ETRAVIRINE

V90I

A98

GL1

00I

K10

1EK

101H

K10

1PK

103N

V106

AV1

06I

V106

MV1

08I

E138

AE1

38K

V179

IV1

79D

V179

FV1

79T

Y181

CY1

81I

Y181

VY1

88C

Y188

HY1

88L

G19

0AG

190S

H22

1YP2

25H

F227

LM

230L

N34

8I

0

5

10

15

20

25

30

35

>40

2.9

10

3.2

Fold

Cha

nge

>40

EFAVIRENZ

V90I

A98

GL1

00I

K10

1EK

101H

K10

1PK

103N

V106

AV1

06I

V106

MV1

08I

E138

AE1

38K

V179

IV1

79D

V179

FV1

79T

Y181

CY1

81I

Y181

VY1

88C

Y188

HY1

88L

G19

0AG

190S

H22

1YP2

25H

F227

LM

230L

N34

8I

0

5

10

15

20

25

30

35

>40

3.03.3

Fold

Cha

nge

* PhenoSense™ cutoff ** Antivirogram® cut-off

A

B>40

NEVIRAPINE

V90I

A98

GL1

00I

K10

1EK

101H

K10

1PK

103N

V106

AV1

06I

V106

MV1

08I

E138

AE1

38K

V179

IV1

79D

V179

FV1

79T

Y181

CY1

81I

Y181

VY1

88C

Y188

HY1

88L

G19

0AG

190S

H22

1YP2

25H

F227

LM

230L

N34

8I

0

5

10

15

20

25

30

35

>40

4.56.0

Fold

Cha

nge

>40

ETRAVIRINE

A98

G+Y

181C

A98

G+G

190A

K10

1E+Y

181C

K10

1E+G

190A

K10

1E+G

190S

K10

1H+Y

181C

K10

1H+G

190A

V179

F+Y1

81C

Y181

C+G

190A

Y181

C+G

190S

0

5

10

15

20

25

30

35

>40

2.9

10

3.2

Fold

Cha

nge

>40

EFAVIRENZ

A98

G+Y

181C

A98

G+G

190A

K10

1E+Y

181C

K10

1E+G

190A

K10

1E+G

190S

K10

1H+Y

181C

K10

1H+G

190A

V179

F+Y1

81C

Y181

C+G

190A

Y181

C+G

190S

0

5

10

15

20

25

30

35

>40

3.03.3

>40

NEVIRAPINE

A98

G+Y

181C

A98

G+G

190A

K10

1E+Y

181C

K10

1E+G

190A

K10

1E+G

190S

K10

1H+Y

181C

K10

1H+G

190A

V179

F+Y1

81C

Y181

C+G

190A

Y181

C+G

190S

0

5

10

15

20

25

30

35

>40

4.56.0

*

*

*

*

*

*

**

**

** **

** ****

>40

ETRAVIRINE

V90I

A98

GL1

00I

K10

1EK

101H

K10

1PK

103N

V106

AV1

06I

V106

MV1

08I

E138

AE1

38K

V179

IV1

79D

V179

FV1

79T

Y181

CY1

81I

Y181

VY1

88C

Y188

HY1

88L

G19

0AG

190S

H22

1YP2

25H

F227

LM

230L

N34

8I

0

5

10

15

20

25

30

35

>40

2.9

10

3.2

Fold

Cha

nge

>40

EFAVIRENZ

V90I

A98

GL1

00I

K10

1EK

101H

K10

1PK

103N

V106

AV1

06I

V106

MV1

08I

E138

AE1

38K

V179

IV1

79D

V179

FV1

79T

Y181

CY1

81I

Y181

VY1

88C

Y188

HY1

88L

G19

0AG

190S

H22

1YP2

25H

F227

LM

230L

N34

8I

0

5

10

15

20

25

30

35

>40

3.03.3

Fold

Cha

nge


A

B>40

NEVIRAPINE

V90I

A98

GL1

00I

K10

1EK

101H

K10

1PK

103N

V106

AV1

06I

V106

MV1

08I

E138

AE1

38K

V179

IV1

79D

V179

FV1

79T

Y181

CY1

81I

Y181

VY1

88C

Y188

HY1

88L

G19

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Figure: Phenotypic resistance of (A) single and (B) double NNRTI mutants to etravirine, nevirapine and efavirenz. Resistant pseudovirions, containing one or two NNRTI mutaNons, were produced by transfecNon into 293T cells. Pseudovirions were tested against serial diluNons of efavirenz, nevirapine and etravirine. The IC50-‐values of each drug-‐virus combinaNon were compared to that of the MJ4 wild-‐type control and Fold-‐Change (FC) values were obtained. Cut-‐off values for both Monogram PhenoSense and Virco AnNvirogram are indicated on the graphs.

Reference: AE Basson, S-‐Y Rhee, CM Parry, T de Oliveira, D Pillay, R Shafer and L Morris. Poster PresentaNon, InternaNonal Workshop on HIV & HepaNNs Virus Drug Resistance and CuraNve Strategies, June 7-‐11, 2011, Los Cabos, Mexico

In adult paMents failing a second-‐line protease inhibitor regimen lopinavir concentraMon measurement in plasma or hair are helpful to exclude paMents with poor adherence from unnecessary resistance tesMng

Background: South African paNents receiving a regimen of LPV/r, didanosine and zidovudine as a second regimen have a high prevalence of virological failure (30-‐40%). This could be due the poor tolerability of the regimen. However problems with adherence are ooen not disclosed. ObjecMve: Therefore objecNve measures of drug exposure such as plasma concentraNon (recent drug use) or hair concentraNon (longer term drug use) could be helpful in idenNfying those paNents with failure despite good adherence who would need resistance tesNng. In a study of paNents failing this second-‐line regimen in 2009 conducted in two public healthcare sites, only 2 of 93 paNents on this regimen had protease inhibitor resistance.

Results: A high lopinavir plasma or hair concentraNon had a negaNve predicNve value of 86% and 89%, for virological failure and the use of both plasma and hair concentraNons could detect all paNents with inadequate drug exposure and who did not have resistance while having virological failure of the regimen. Conclusion: We therefore propose that lopinavir hair and or plasma measurement should form part of the work-‐up of paNents failing a second-‐line boosted protease inhibitor regimen to exclude paNents with inadequate adherence from genotypic anNretroviral resistance tesNng.


14

SATuRN: Report 2011


15

Figure: ScaEerplot of Lopinavir (ng/mg) and plasma concentraNons [(μg/mL) in paNents with virologic failure (triangles) and nonfailure paNents (open circles)]. The dashed lines indicate the respecNve concentraNon cut-‐offs: LPV plasma concentraNon of 1 μg/mL and LPV hair concentraNon of 3.64 ng/mg.

Reference: van Zyl GU, van Mens TE, McIlleron H, Zeier M, Nachega JB, Decloedt E, Malavazzi C, Smith P, Huang Y, van der Merwe L, Gandhi M, Maartens G. Low Lopinavir Plasma or Hair ConcentraNons Explain Second-‐Line Protease Inhibitor Failures in a Resource-‐Limited Se_ng. J Acquir Immune Defic Syndr 2011;56:333–339.

LPV Plasma concentraNon ⏏ Virologic failure ¢ no virologic failure

Hair LPV concen

traN

on

HIV clinical management: IntegraMng virtually failure clinics in southern Africa.

IntroducMon: Several years into the ART rollout program in South Africa, some paNents are beginning to fail their first or second-‐line drug regimens. Data on HIV drug resistance and its impact on the management of paNents with subtype C viruses is limited. InformaNon on resistance associated mutaNons at clinical outcome of paNents is needed to guide treatment opNons and ensure that South Africa’s ART program is highly effecNve.

HIV Drug Resistance InterpretaMon: HIV Drug Resistance TesNng Process: RT and protease were sequenced using a discounted in-‐house genotyping method, which is freely distributed by SATuRN (more info on this method on page 14 of this report). Data was submiEed to SATuRN RegaDB Clinical Database for confirmaNon of sequence quality and idenNficaNon of PI, NNRTI and NRTI resistance mutaNons. A resistance report is produced together with clinical tests and treatment informaNon (an example is seen on page 10 of this report).

HIV Treatment Failure Clinic InterpretaMon Model: A resistance report is generated using RegaDB/Stanford HIVDB algorithms. The clinical chart and resistance results are interpreted by an InfecNous Disease (ID) specialist in Pretoria (Dr. Theresa Rossouw) or Bloemfontein (Dr. Cloete van Vuuren), who suggests the best possible treatment opNon based on the drugs that are available through the Department of Health in South Africa. The report is sent to the physician managing the paNent, who can contact the I.D. specialist for further discussion.

Virtual Failure Clinic meeMngs: A virtual failure clinic meeNng is schedule twice a month on Wednesdays, 8am-‐9am. During these meeNngs, two clinical cases are presented together with literature on the subject. These meeNngs are chaired by Dr. Theresa Russouw (UP), Dr. Cloete Van Vuuren (UFS) and Dr. Kevi Naidu (Africa Centre).


16

SATuRN: Report 2011


1. Monitor viral load, CD4 and drug regimen of a paMent on ART

2. PopulaMon RNA/DNA sequencing of PR and RT genes

3. Enter mutaMons into algorithm to select opMmal new

treatment regimen

-‐  rise in viral load indicates resistance may be emerging

-‐  compare to reference sequence to idenNfy resistance mutaNons

-‐  change regimen based on algorithm results

HIV ARV Drug Resistance TesNng Process

Figure I: HIV anNretroviral drug resistance tesNng process in SATuRN involves three major steps: 1. PaNent monitoring and blood sampling, 2. Genotyping and sequencing, 3. BioinformaNcs analysis and clinical interpretaNon of the case, as detailed in figure II.

How to parMcipate in the virtual failure clinics: These meeNngs are targeted at clinicians, clinical virologists, researchers and post-‐graduate students who are currently involved in the treatment of paNents with ARVs in Southern Africa. ParNcipants need to register with SATuRN in advance and will join via conference call.

Contact InformaMon: Lungani Ndwandwe SATuRN Research Assistant Africa Centre for Health and PopulaNon Studies, University of KwaZulu-‐Natal, Somkhele -‐ South Africa. Tel : (035) 550 7500 Fax: (035) 550 7565 e-‐mail : [email protected] Chairs e-‐mails: [email protected], [email protected] & [email protected]

17

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18

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SATuRN: Report 2011


19

Southern African HIV Drug Resistance and Clinical Management Workshop

IntroducMon: The Southern African Drug Resistance and Clinical Management Workshop is presented every year. The workshop includes theoreNcal lectures and pracNcal sessions on the usage and interpretaNon of HIV-‐1 drug resistance genotyping in the management of HIV paNents on anN-‐retroviral (ARV) treatment. This workshop is targeted at clinicians, clinical virologists, nurses, medical students and researchers working in the public and private sector who are currently involved in the treatment of paNents with ARVs in Southern Africa.

Successful past and promising future: The 4th and 5th workshops were presented at the University of the Free State (UFS) Medical School in 2009 and 2010. This workshop, to the best of our knowledge, is now considered the top regional meeNng on HIV drug resistance and clinical management. In total we have trained nearly 1,000 physicians and nurses as part of this workshop. For example, in 2010 we got 436 applicaNons and 215 parNcipants aEended the workshop, represenNng in total 17 countries. We also had 22 presenters. These included the CDC/PEPFAR Chief of the AIDS Treatment and Care Branch in South Africa, Prof. Jeffrey Klausner, the director of the HIV resistance program from the World Health OrganizaNon, Dr. Michael Jordan and some of the top internaNonal and naNonal HIV clinicians and researchers.


20

1st to 5th workshop was organized by:

SATuRN: Report 2011



Figure: Trend in the prevalence of TDR between 2000 and 2010

See you in Gaborone! The 6th Southern African HIV Drug Resistance and Clinical Management Workshop, 7 to 8 October 2011, Gaborone, Botswana.

21

Funded by:

SATuRN and Life Technologies (ABI) partnership provide a discounted HIV resistance genotyping system.

IntroducMon: AnNretroviral (ARV) drugs are becoming increasingly available to treat HIV-‐1 infected individuals in the developing world. The goal of many governments and non-‐governmental organizaNons is to sustain the effecNve ARV treatment of > 5 million people in Africa. PharmaceuNcal companies are reducing both prices and internaNonal trade restricNons on patented drugs to allow more equitable access to essenNal medicines for AIDS, TB and Malaria. However, the widespread increase of treatment is threatened by the appearance of drug resistance. Public health and paNent benefit may be limited by the increase in selecNon and transmission of broadly ARV resistant viruses. Drug resistance viruses can currently be idenNfied with geneNc sequencing of two HIV-‐1 genes. However, the price of an individual test using commercial methods (ZAR 2,500 – US$ 300) makes it too expensive for public health implementaNon in southern Africa. SATuRN HIV Resistance Genotyping We have developed an in-‐house HIV resistance genotyping system in collaboraNon with the Stanford HIV Drug Resistance Database team and it has been internaNonally validated by the French AIDS Research (French acronym: ANRS).

Our in-‐house sequences are generated with the Sanger ABI sequencing technology. This process involves the producNon of cDNA, which is reverse transcribed from the viral RNA. Our in-‐house genotyping test reagents currently costs around ZAR 750 (US$ 100) per sample, a great part of the cost of which ZAR560/ZAR750 (US$80/US$100) is due to the cDNA synthesis and the ABI sequencing process. SATuRN members would like to ask ABI to reduce the price of the reagents needed for HIV drug resistance genotyping for the members of our network. Life Technologies (ABI) and SATuRN partnership: Life Technologies has agreed to provide a 25% discount for reagents for HIV genotyping to SATuRN members. This partnership aims to produce a ‘discounted genotypic test kit’ to southern African partners that will be available soon. For the moment, partners can request discounted reagents from ABI (Seshnee Pillay, [email protected]) and the protocol and validaNon samples from SATuRN partners at the UFS (Dr. Dominique Goedhals, [email protected]) and Africa Centre (Justen Manasa, [email protected]).


22

SATuRN: Report 2011


HIV Drug Resistance Satellite MeeMng of the 5th South African AIDS Conference

The HIV Drug Resistance Satellite session: We would like to bring to your aEenNon the HIV Drug Resistance Satellite MeeNng of the 5th South African AIDS Conference, on 7 June 2011 (9am – 1pm), at the InternaNonal Conference Centre (ICC), Durban, South Africa. The meeNng includes theoreNcal lectures and clinical cases on the usage and interpretaNon of HIV-‐1 drug resistance genotyping in the management of HIV paNents on anN-‐retroviral (ARV) treatment. This meeNng is targeted at clinicians, clinical virologists, nurses, medical students and researchers working in the public and private sector who are currently involved in the treatment of paNents with ARVs in Southern Africa.

Presenters: Prof. Jeffrey Klausner, CDC/PEPFAR. Prof. Wendy S Stevens, Wits and NHLS Prof. Francesca Conradie, Wits Dr. Gillian Hunt, NICD Dr. Tulio de Oliveira, Africa Centre.

Contact InformaMon: Helen Savva Health CommunicaNons Specialist U.S. Centers for Disease Control and PrevenNon Global AIDS Program -‐-‐ South Africa Tel : (012) 424 9026 Fax: (012) 346 4286 e-‐mail : [email protected]

23


Acknowledgements

Funding: SATuRN drug resistance databases, failure clinic system, research and training components are partly funded by: The US Center for Diseases Control (CDC), the PresidenNal Plan for AIDS Relief (PEPFAR), the European Commission (EC), the Wellcome Trust and the CISR Swiss South African Joint Research Programme (SSJRP). CoordinaMng Centre: Africa Centre for Health and PopulaNon Studies – Dr. Tulio de Oliveira South African Medical Research Council – Prof. Chris Seebregts Collaborators: Dr. Ashraf Grimwood, CEO, Kheth’Impilo, South Africa. Dr. Ava Avalos, Dr. Tendani Gaolathe, Dr. Madisa Mine, Botswana Ministry of Health and Botswana/Harvard Partnership. Dr. Carole Wallis and Prof. Wendy S. Stevens, Department of Molecular Medicine and Haematology, University of the Witwatersrand and the NaNonal health Laboratory Service, South Africa. Dr. Cloete van Vuuren, Dr. Dominique Goedhals, Dr. Dewald Steyn, Medical School, University of the Free State, South Africa.

Dr. Diana Dickinson, private clinician, Gaborone, Botswana. Dr. Gert van Zyl, Prof. Susan Engelbretch, Prof. Wolfgang Preiser, Division of Medical Virology, Department Pathology, NHLS, Tygerberg and Stellenbosch University, South Africa. Dr. Gillian Hurt, NaNonal InsNtute of Communicable Diseases, Johannesburg, South Africa. Dr. Ricardo Jorge Gonçalves Ornelas Camacho, InsNtuto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Portugal. Dr. Soo-‐Yon Rhee, Tommy Liu and Prof. Robert Shafer, Stanford University, USA. Dr. Tulio de Oliveira, Justen Manasa, Dr. Richard Lessells, Dr. Kevi Naidu, Dr. Ruth Bland and Prof. Marie-‐Louise Newell, from the Africa Centre for Health and PopulaNon Studies, University of KwaZulu-‐Natal, Somkhele, South Africa. Dr. Ziad El-‐KhaNb, Division of Global Health, Karolinska InsNtutet, Sweden Prof. Anne-‐Mieke Vandamme, Laboratory for Clinical and Epidemiological Virology, AIDS Reference Laboratory, Rega InsNtute, Katholieke Universiteit Leuven, Belgium. Prof. Chris Seebregts, Medical Research Council, Cape Town, South Africa. Prof. ChrisNna Zarowsky, Prof. Debra J Jackson, School of Public Health, University of the Western Cape, South Africa.


24

Collaborators: Prof. Christopher Hoffmann, Aurum InsNtute for Health Research, Johannesburg, South Africa. Prof. David Katzenstein, Stanford University, USA. Prof. Lynn Morris, NaNonal InsNtute of Communicable Diseases, Johannesburg, South Africa. Prof. Lynne M. Webber, Head of Department of Medical Virology, University of Pretoria, South Africa. Prof. Rami Kantor, Brown University, USA. Prof. Robin Wood, Prof. Catherine Orrell, Desmond Tutu HIV Centre, University of Cape Town, South Africa. Prof. Sharon Cassol and Dr. Theresa Rossouw, University of Pretoria, South Africa. Prof. Thumbi Ndung'u and Dr. Michelle Gordon, HIV Pathogenesis Programme, Doris Duke Medical Research InsNtute, University of KwaZulu-‐Natal, South Africa. Secretariat: SATuRN is grateful for the help provided in the organizaNon of our meeNngs and research programs. We would like to thanks: Anthea Van Blerk, South African Medical Research Council. Emma Chademana &Tamlin Petersen, School of Public Health, University of the Western Cape. Zethu Luthuli & Sonja Andrews, Africa Centre for Health and PopulaNon Studies, UKZN.

PublicaMons: -‐ de Oliveira T, Shafer WR, Seebregts C. Public Database for HIV Drug Resistance in southern Africa. (2010) Nature, 464(7289):673. -‐ El-‐KhaNb Z, Ekström AM, Ledwaba J, Mohapi L, Laher F, Karstaedt A, Charalambous S, Petzold M, Katzenstein D, Morris L. Viremia 1 and drug resistance among HIV-‐1 paNents on anNretroviral treatment – a cross secNonal study in Soweto, South Africa. AIDS. 2010 Jul 17;24(11):1679-‐87.PMID: 20453629. -‐ El-‐KhaNb Z, Ekstrom AM, Coovadia A, Abrams EJ, Petzold M, Katzenstein D, Morris L, Kuhn L. Adherence and virologic suppression during the first 24 weeks on anNretroviral therapy among women in Johannesburg, South Africa -‐ a prospecNve cohort study. BMC Public Health. 2011 Feb 8;11(1):88. [Epub ahead of print] -‐ Dalai SC, de Oliveira T, Harkins GH, Kassaye SG, Lint J, Manasa J, Johnston E, Katzenstein D. EvoluNon and Molecular Epidemiology of HIV-‐1 Subtype C in Zimbabwe. (2009) AIDS, 23(18):2523-‐32. -‐ Huang KH, Goedhals D, Fryer H, van Vuuren C, Katzourakis A, de Oliveira T, Brown H, Cassol S, Seebregts C, McLean A, Klenerman P, Phillips R, Frater. Prevalence of HIV type-‐1 drug associated mutaNons in pre-‐therapy paNents in the Free State, South Africa.(2009) AnNvir Ther.,14(7):975-‐984.

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PublicaMons: -‐ El-‐KhaNb Z, DeLong AK, Katzenstein D, Ekstrom AM, Ledwaba J, Mohapi L, Laher F, Petzold M, Morris L, Kantor R. Drug Resistance PaEerns and Virus Re-‐Suppression among HIV-‐1 Subtype C Infected PaNents Receiving Non-‐Nucleoside Reverse Transcriptase Inhibitors in South Africa. J AIDS Clinic Res 2011, 2:2 -‐ El-‐KhaNb Z, Katzenstein D, Marrone G, Laher F, Mohapi L, Petzold M, Morris L, Ekström AM Adherence to Drug-‐Refill Is a Useful Early Warning Indicator of Virologic and Immunologic Failure among HIV PaNents on First-‐Line ART in South Africa. PLoS One. 2011 Mar 9;6(3):e17518. -‐ Murrell B, de Oliveira T, Seebregts C, KosakovskyPond SL, Scheffler K. Modeling HIV-‐1 drug resistance as episodic direcNonal selecNon. Molecular Biology and EvoluNon, submiEed. -‐ de Oliveira T, Gordon M, Cassol E, Murrell B, Seebregts C, Bland R, Newell ML, Cassol S. Use of SelecNon Pressure Analysis for the Surveillance of HIV-‐1 Drug Resistance. Retrovirology, submiEed. -‐ Karim QA, Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany ABM, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D on behalf of the CAPRISA 004 Trial Group. EffecNveness and safety of Tenofovir gel, and anNretroviral microbicide, for the prevenNon of HIV infecNon in women. Science 2010: 329: 1168-‐1174

-‐ Coovadia A, Abrams EJ, Stehlau R, Meyers T, Martens L, Sherman G, Hunt G, Hu CC, Tsai WY, Morris L, Kuhn L. Re-‐use of nevirapine in HIV-‐infected children aoer suppression with a protease inhibitor-‐based treatment regimen. JAMA. 2010: 304 (10): 1082-‐1090 -‐ Taylor BS, Hunt G, Abrams EJ, Coovadia A, Meyers T, Sherman G, Strehlau R, Morris L, Kuhn L. Rapid development of anNretroviral drug resistance mutaNons in HIV-‐infected children iniNaNng protease inhibitor-‐based therapy less than 2 years of age in South Africa -‐ Hunt GM, Coovadia A, Abrams EJ, Sherman G, Meyers T, Morris L, Kuhn L. HIV-‐1 drug resistance at anNretroviral treatment in children previously exposed to single-‐dose nevirapine. AIDS (In press) -‐ Dlamini JN, Hu Z, Ledwaba J, Morris L, Maldarelli FM, Dewar RL, HighbargerHC, Somaroo H, Sangweni P, Follmann DA, Pau AK. Genotype Resistance at Viral Rebound among PaNents who received Lopinavir/Ritonavir – or Efavirenz-‐Based First AnNretroviral Therapy in South Africa. JAIDS (In press) -‐ Azzoni L, Firnhaber C, Foulkes AS, Gross R, Yin X, Van Amsterdam D, Schulze D, Glencross DK, Stevens W, Hunt G, Morris L, Fox L, Sanne I, Montaner LJ. Randomized Trial of Time-‐Limited InterrupNons of Protease Inhibitor-‐based AnNretroviral Therapy (ART) vs. ConNnuous Therapy for HIV-‐1 InfecNon. PLoS ONE (In press) -‐ Hunt GM, Ledwaba J, Basson AE, Moyes J, Cohen C, Singh B, Bertagnolio S, Jordan MR, Puren A, Morris L. Surveillance of TransmiEed HIV-‐1 Drug Resistance in South Africa from 2005-‐2009. CID (SubmiEed)


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PublicaMons: -‐ van Zyl GU, van Mens TE, McIlleron H, Zeier M, Nachega JB, Decloedt E, Malavazzi C, Smith P, Huang Y, van der Merwe L, Gandhi M, Maartens G. Low Lopinavir Plasma or Hair ConcentraNons Explain Second-‐Line Protease Inhibitor Failures in a Resource-‐Limited Se_ng. J Acquir Immune Defic Syndr 2011;56:333–339. -‐ van Zyl GU, CoEon MF, Claassen M, Abrahams C, Preiser W. Surveillance of transmiEed resistance to anNretroviral drug classes among young children in the Western Cape Province of South Africa. Pediatr Infect Dis J. 2010, 29(4):370-‐1. -‐ van Zyl GU, van der Merwe L, Claassen M, CoEon MF, Rabie H, Prozesky HW, Preiser W. Protease inhibitor resistance in South African children with virologic failure. Pediatr Infect Dis J. 2009 Dec;28(12):1125-‐7. Abstracts: -‐ Van Vuuren C, Goedhals D, Steyn D, Mamabolo MK, Monyane R, Murrell B, Cassol S, de Oliveira T, Seebregts C. HIV Drug resistance in adult paNents failing first-‐line anNretroviral therapy (ART) in the Free State Province of South Africa. IAS 2011, Rome, Italy. -‐Goedhals D Van Vuuren C, Steyn D, Mamabolo MK, Monyane R, Murrell B, Cassol S, de Oliveira T, Seebregts C. Low Level of Protease Inhibitor (PI) Resistance in PaNents Failing Second Line Drug Regimens in the Free State Province of South Africa. IAS 2011, Rome, Italy.

-‐ Wilkinson E, de Oliveira T, Engelbretch S. History and EvoluNon of the Subtype C HIV-‐1 Epidemic in Southern Africa. Poster the 18th InternaNonal HIV, Dynamics and EvoluNon Workshop, May 1-‐4, 2011, Galway, Ireland. -‐ Wallis C, H Ribaudo, D Katzenstein, E Aga, S Saravanan, M Norton, B Kallungal, J BartleE, N Kumarasamy, W StevensPaEern of Drug Resistance MutaNons among Non-‐subtype B Viruses following First-‐line ART Failure at Screening to ACTG 5230 in Resource-‐limited Se_ngs. Paper # 616. Presented at the 18th Conference on Retroviruses and OpportunisNc InfecNons, February 27-‐March 2, 2011. Boston, MA. -‐ Murrell B, de Oliveira T, Seebregts C, Kosakovsky Pond SL, Scheffler K. Modeling HIV-‐1 drug resistance as episodic direcNonal selecNon. Oral presentaNon at the 18th InternaNonal HIV, Dynamics and EvoluNon Workshop, May 1-‐4, 2011, Galway, Ireland -‐ El-‐KhaNb Z, D Katzenstein, J Ledwaba, F Laher, M Maphutha, S Kassaye, L Mohapi, M Petzold, A Ekstrom, L Morris, and South African Adherence and Virlogic EvaluaNon (SAVE) Study Group. Adherence and Drug Resistance in an HIV Treatment Program in South Africa. Abstract 668, Presented at the Conference on Retroviruses and opportunisNc infecNons, Montreal 2009.

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Abstracts: -‐Manasa J, Cassol S, Seebregts C, Newell ML , de Oliveira T Tracing twenty years of primary drug resistance studies in South Africa. 5th SA AIDS Conf, Durban, South Africa. -‐ de Oliveira T, Gordon M, Cassol E, Murrell B, Seebregts C, Bland R, Newell ML, Cassol S. Use of SelecNon Pressure Analysis for the Surveillance of HIV-‐1 Drug Resistance. 5th SA AIDS Conf, Durban, South Africa. -‐ Rossouw T, Mahasha P , G. Malherbe, J. Manasa, G. van Dyk, S Cassol, C Seebregts, T de Oliveira. SATuRN, the Southern African Treatment and Resistance Network: ApplicaNon to the Management and Surveillance of HIV-‐1 Drug Resistance in a Public Health Se_ng in Pretoria. 5th SA AIDS Conf, 2011, Durban, South Africa. -‐ Wilkinson E, de Oliveira T, Engelbretch S. History and EvoluNon of the Subtype C HIV-‐1 Epidemic in Southern Africa. Poster at 5th SA AIDS Conf, 2011, Durban, South Africa. -‐ Kantor R, A DeLong, J Ledwaba, A Kamau, J McIntyre, L Morris and D Katzenstein for the South African Treatment and Resistance Network (SATuRN). AssociaNon between mutaNons affects drug resistance selecNon by single-‐dose nevirapine inHIV-‐1 subtype C. AnNviral Therapy 2009, 14 Suppl 1:A159 Presented at the XVIII InternaNonal Drug Resistance Workshop, Ft. Meyers, Fl. June 9-‐12, 2009.

-‐ Kamau A, CJ Seebregts, D Katzenstein, R Kantor, S Cassol, J Ledwaba, L Morris, C Hoffman and T de Oliveira for the South African Treatment and Resistance Network (SATuRN). Itemset mining: an approach to idenNfy co-‐occurrence of drug resistance mutaNons among HIV-‐1-‐infected paNents failing therapy ABSTRACT 162 AnNviral Therapy 2009, 14 Suppl 1:A185 Presented at the XVIII InternaNonal Drug Resistance Workshop, Ft. Meyers, Fl. June 9-‐12, 2009 -‐ Banks L, E. White, D. Katzenstein. Drug resistance and suscepNbility genotype from proviral DNA and circulaNng RNA among subtype C HIV-‐1 infected paNents. Abstract TUAA0202 Presented at the AIDS 2008 • XVII InternaNonal AIDS Conference • 3-‐8 August 2008, Mexico. City.


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For more informaMon on how to parMcipate in SATuRN acMviMes and how to contribute published and unpublished data to the SATuRN drug resistance databases, please contact: Tulio de Oliveira Africa Centre for Health and PopulaNon Studies, University of KwaZulu-‐Natal, Somkhele -‐ South Africa. Tel : +27 35 550 7500 Fax: +27 35 550 7565 e-‐mail : [email protected] Chris Seebregts South African Medical Research Council Tel: +27 21 938 0318 Fax: +27 86 683 2449 E-‐mail: [email protected] David Katzenstein Division of infecNous Disease Stanford University Medical Center S-‐140 Grant Bldg. 300 Pasteur Drive Stanford California 94305 Tel. 650-‐725-‐8304 E-‐mail: [email protected]

Rami Kantor Division of InfecNous Diseases Brown University Alpert Medical School The Miriam Hospital, RISE 154 164 Summit Avenue Providence, RI 02906 Tel: 401-‐7934997 E-‐mail: [email protected] Lynn Morris & Gillian Hunt AIDS Unit at the NaNonal InsNtute for Communicable Diseases (NICD) Johannesburg, South Africa E-‐mails: [email protected] & [email protected] For deposiNng published data at Stanford HIVdb, please contact: Robert Shafer & Soo-‐Yon Rhee Stanford HIV Drug Resistance Database, Stanford University S-‐140 Grant Bldg. 300 Pasteur Drive Stanford California 94305 Tel: +1 650 725-‐2946 Email:S [email protected] & [email protected]

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Funded by:

Disclaimer: The SATuRN consorNum wishes to express its graNtude to the following funders for their generous support for the producNon of this report: European Commission (EC), Centers for Disease Control and PrevenNon (CDC), President's Emergency Plan for AIDS Relief (PEPFAR), InternaNonal Development Research Centre (IDRC), Council for ScienNfic and Industrial Research (CSIR) and the Wellcome Trust. The report is published as open access under a CreaNve Commons ShareAlike 3.0 Unported (CC BY-‐SA 3.0) license (hEp://creaNvecommons.org/licenses/by-‐sa/3.0/) and is available in printed format as well as electronically as PDF, Google books, iBooks, Web-‐format, etc. The contents of this report and the opinions expressed herein are solely the responsibility of the authors and do not necessarily represent the official views or policies of any of the funders.

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