Treatment failure and drug resistance is more frequent in HIV-1 subtype D versus subtype A-infected Ugandans over a 10-year study period

Abstract

Objectives: To determine the impact of HIV-1 subtype on treatment outcomes and the emergence of drug resistance in the resource limited setting of Kampala, Uganda.

Design: The Joint Clinical Research Centre (JCRC) in Kampala, Uganda has provided over 2000 drug-resistant genotypes (DRGs) over the past 10 years as standard of care for patients failing therapy and 1403 from treatment-naive and experienced patients over the past 10 years have been analyzed for this study.

Method: Viral loads, CD4 cell count, treatment histories and other relevant clinical data was compared with the infecting HIV-1 subtype and DRGs of Ugandan patients failing treatment.

Results: Patients failing HAART with DRGs (n = 937) were more frequently infected with subtype D than expected on the basis of the subtype distribution in the treatment-naive population (n = 655) in Kampala (P < 0.001). Higher proportions of treatment failures among subtype D-infected patients were driven by resistance to nucleoside reverse transcriptase inhibitors (NRTI) (P < 0.0002) more than to non-NRTIs (P > 0.04) or protease inhibitors.

Conclusion: Higher rates of treatment failure among subtype D as compared with subtype A-infected Ugandans was analogous to the faster disease progression in subtype D-infected patients. The mechanism(s) by which drug resistance may emerge faster in subtype D HIV-1 may relate to higher replicative fitness and increased propensity for a CXCR4 tropism.

Fig. 1. Summary of drug resistance genotype testing performed on treatment-naive and treatment-experienced HIV-infected patients at the Joint Clinical Research Centre (JCRC), Kampala, Uganda over a 10-year period

The number of drug resistance genotypes (DRGs) performed on samples from treatment failures (a and b) and treatment-naive patients (c and d) over the past 10 years are presented as a percentage with at least one primary drug-resistant mutation (a and c) or based on the infecting HIV-1 subtype in the sample (b and d).

Fig. 2. CD4 cell count and viral loads before and after drug resistance genotyping in Joint Clinical Research Centre (JCRC) patients

Viral loads (a) and CD4 cell count (b) were measured 1–5 year and 3 months in patients prior to obtaining a drug resistance genotype (DRG). These analyses were also performed within 3 months of the DRG or 12–15 months and 1–5 years following the DRG. Only one CD4 or viral load measurement per patient (with DRG) was factored into the 3 month and 12–15 month analyses. The 1–5 year analyses of CD4 cell count and viral loads before or after the DRG involved several values per patient when available. In (a) *refers to the highest outlying viral load that is scaled by the Y axis. In (b) the highest CD4 cell count is provided as a number, e.g. ‘* = 3893’. yrs, years; mo, months.

Fig. 3. Frequency of drug resistance mutations in subtype A and D HIV-1 failing antiretroviral treatment from 1998 to 2009

The frequency of drug resistance mutations per subtype A (a, b, and f) or subtype D samples (c, d, and e) was examined for this treatment failure cohort. The mutations in reverse transcriptase to nucleoside reverse transcriptase inhibitors (NRTI) in each subtype A-infected patient is shown by single green dot across the reverse transcriptase (a). The frequency of each NRTI mutations within the subtype A population is described in (b) and for subtype D in (c). For the NNRTI resistance mutations, the individual mutations per DRG test for each year is shown in (d) for subtype D infections. The frequency of each NNRTI mutation within the subtype D population is described in (e) and for subtype A in (f).

Fig. 4. Comparing the distribution in HIV-1 subtypes in the treatment-naive population and in patients failing antiretroviral treatment

The percentage of subtypes A, B, C, D, and unique recombinant forms in the treatment naive population is shown as the first set of bars in panels a, b, and c. Percentage of subtypes in all DRG tests performed on reverse transcriptase coding region are in the second set of bars followed by the subtype percentage in only those samples harboring primary drug resistance mutations. The next set of bars describes the subtype percentages in those samples harboring primary resistance mutations to a specific nucleoside reverse transcriptase inhibitor (NRTI), tenofovir (TDF), and nonnucleoside reverse transcriptase inhibitor (NNRTI). Panel (a) describes the subtype distributions for all patient samples failing any antiretroviral treatment regimen, (b) only those failing first line HAART (one NNRTI + one cytidine analog + one thymidine analog), and (c) only those failing a second line or subsequent salvage regimens. ABC, abacavir; D4T, stavudine; ddI, didanosine; DLV, delaviridine; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; NVP, nevirapine; TDF, tenofovir; ZDV, zidovudine; 3TC, lamivudine.